EP1244446B1 - Thrombopoietin-mimetika - Google Patents

Thrombopoietin-mimetika Download PDF

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Publication number
EP1244446B1
EP1244446B1 EP00984123A EP00984123A EP1244446B1 EP 1244446 B1 EP1244446 B1 EP 1244446B1 EP 00984123 A EP00984123 A EP 00984123A EP 00984123 A EP00984123 A EP 00984123A EP 1244446 B1 EP1244446 B1 EP 1244446B1
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Prior art keywords
hydroxy
imidazole
naphth
sulfonic acid
naphtho
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French (fr)
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EP1244446A4 (de
EP1244446A1 (de
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Juan I. GlaxoSmithKline LUENGO
Kevin J. GlaxoSmithKline DUFFY
Alan T. GlaxoSmithKline PRICE
Lihua GlaxoSmithKline ZHANG
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to thrombopoietin (TPO) mimetics and their use as promoters of thrombopoiesis and megakaryocytopoiesis.
  • TPO thrombopoietin
  • Megakaryocytes are bone marrow-derived cells, which are responsible for producing circulating blood platelets. Although comprising ⁇ 0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells. See Kuter et al. Proc. Natl. Acad. Aci. USA 91: 11104-11108 (1994). Megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polypoid cells. In response to a decreased platelet count, the endomitotic rate increases, higher ploidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold. See Harker J. Clin. Invest . 47: 458-465 (1968). In contrast, in response to an elevated platelet count, the endomitotic rate decreases, lower ploidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%.
  • TPO thrombopoietin
  • TPO is thought to affect megakaryocytopoiesis in several ways: (1) it produces increases in megakaryocyte size and number; (2) it produces an increase in DNA content, in the form of polyploidy, in megakaryocytes; (3) it increases megakaryocyte endomitosis; (4) it produces increased maturation of megakaryocytes; and (5) it produces an increase in the percentage of precursor cells, in the form of small acetylcholinesterase-positive cells, in the bone marrow.
  • TPO platelets
  • thrombocytes are necessary for blood clotting and when their numbers are very low a patient is at risk of death from catastrophic hemorrhage
  • TPO has potential useful application in both the diagnosis and the treatment of various hematological disorders, for example, diseases primarily due to platelet defects.
  • Ongoing clinical trials with TPO have indicated that TPO can be administered safely to patients.
  • recent studies have provided a basis for the projection of efficacy of TPO therapy in the treatment of thrombocytopenia, and particularly thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transplantation as treatment for cancer or lymphoma. See e.g., McDonald (1992) Am. J. Ped. Hematology/Oncology 14: 8-21 (1992).
  • Thrombopoietin is a glycoprotein with two distinct regions separated by a potential Arg-Arg cleavage site.
  • the amino-terminal region is highly conserved in man and mouse, and has some homology with erythropoietin and interferon-alpha and interferon-beta.
  • the carboxy-terminal region shows wide species divergence.
  • TPO-R human TPO receptor
  • c-mpl human TPO receptor
  • TPO-R as a key regulator of megakaryopoiesis is the fact that exposure of CD34 + cells to synthetic oligonucleotides antisense to TPO-R RNA significantly inhibits the appearance of megakaryocyte colonies without affecting erythroid or myeloid colony formation.
  • a first aspect of this invention relates to a medicament for use in therapy, manufactured using and comprising a compound having Formula (II): in which R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of: carboxylic acid, sulfonic acid, hydrogen, C 1-6 alkoxy, C 1-6 alkyl and halogen; R 6 is hydrogen; R 7 is selected from the group consisting of: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl and substituted alkyl; m is 0 - 3; and AR is cyclic or polycyclic aromatic C 3 -C 14 , optionally containing from one to three heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, C 1 -C 12 aryl, substituted
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from carboxylic acid, sulfonic acid, hydrogen, C 1-3 alkoxy, C 1-3 alkyl and halogen;
  • R 6 is hydrogen;
  • R 7 is selected from hydrogen, alkyl and substituted alkyl;
  • m is 0;
  • AR is selected from naphthalene, phenyl, pyridine and pyrazole, and is optionally substituted with from one to three substituents selected from the group consisting of alkyl, substituted alkyl, C 1 -C 12 aryl, substituted C 1- C 12 aryl, hydroxy, amino, -NR 11 R 11 , alkoxy and halogen, where R 11 is selected from the group consisting of: hydrogen, alkyl, cycloalkyl, C 1- C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl; and
  • a second aspect of the invention provides a compound having the following Formula (IIA): in which R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from carboxylic acid, sulfonic acid, hydrogen, C 1-3 alkoxy, C 1-3 alkyl and halogen; R 6 is hydrogen; R 7 is selected from hydrogen, alkyl and substituted alkyl; m is 0; and AR is selected from naphthalene, phenyl, pyridine and pyrazole, and optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C 1 -C 12 aryl, substituted C 1 -C 12 aryl, hydroxy, alkoxy and halogen; and wherein by the term "alkyl", and in derivatives thereof, is meant a linear or branched, saturated or unsaturated hydrocarbon chain, which unless otherwise defined has C 1 -C 12 carbon atoms; and pharmaceutically acceptable salts,
  • the compounds can be used in a method of treating thrombocytopenia, which comprises administering to a subject in need thereof an effective amount of a TPO mimetic compound of Formula (II) or (IIA).
  • the present invention also relates to the discovery that the compounds of Formula (II) and (IIA) are active as agonists of the TPO receptor.
  • compositions comprising a pharmaceutical carrier and compounds useful in the methods described in the invention.
  • the present invention also describes methods of co-administering the presently invented TPO mimetic compounds with further active ingredients.
  • Preferred among the presently invented compounds are the following compounds; and a third aspect of the invention provides a compound which is selected from the following compounds:
  • aryl as used herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic ring containing from 1 to 14 carbon atoms and optionally containing from one to five heteroatoms, provided that when the number of carbon atoms is 1 the aromatic ring contains at least four heteroatoms, when the number of carbon atoms is 2 the aromatic ring contains at least three heteroatoms, when the number of carbons is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom.
  • C 1 -C 12 aryl as used herein, unless otherwise defined, is meant phenyl, naphthalene, 3,4-methylenedioxyphenyl, pyridine, biphenyl, quinoline, pyrimidine, quinazoline, thiophene, furan, pyrrole, pyrazole, imidazole and tetrazole.
  • substituted as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of: hydroxyalkyl, alkoxy, acyloxy, alkyl, amino, N-acylamino, hydroxy, -(CH 2 ) g C(O)OR 6 , -S(O) n R 7 , nitro, cyano, halogen, trifluoromethyl and protected -OH, where g is 0-6, R 6 is hydrogen or alkyl, n is 0-2, and R 7 is hydrogen or alkyl.
  • alkoxy as used herein is meant -Oalkyl where alkyl is as described herein including -OCH 3 and -OC(CH 3 ) 2 CH 3 .
  • cycloalkyl as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C 3 -C 12.
  • cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4-methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl and cyclopentyl.
  • acyloxy as used herein is meant -OC(O)alkyl where alkyl is as described herein.
  • Examples of acyloxy substituents as used herein include: -OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 and -OC(O)(CH 2 ) 3 CH 3 .
  • N-acylamino as used herein is meant -N(H)C(O)alkyl, where alkyl is as described herein.
  • Examples of N-acylamino substituents as used herein include: -N(H)C(O)CH 3 , -N(H)C(O)CH(CH 3 ) 2 and -N(H)C(O)(CH 2 ) 3 CH 3 .
  • aryloxy as used herein is meant -OC 6 -C 12 aryl where C 6 -C 12 aryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl optionally substituted with one or more substituents selected from the group consisting of: alkyl, hydroxyalkyl, alkoxy, trifuloromethyl, acyloxy, amino, N-acylamino, hydroxy, -(CH 2 ) g C(O)OR 6 , -S(O) n R 7 , nitro, cyano, halogen and protected -OH, where g is 0-6, R 6 is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl.
  • substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.
  • heteroatom oxygen, nitrogen or sulfur.
  • halogen as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride.
  • alkyl and derivatives thereof and in all carbon chains as used herein is meant a linear or branched, saturated or unsaturated hydrocarbon chain having C 1 -C 12 carbon atoms.
  • treating and derivatives thereof as used herein, is meant prophylatic or therapeutic therapy.
  • esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • R SO3H i) 4-amino-1-benzenesulfonic acid, NaNO 2 , NaHCO 3 water; ii) HCl, ice; iii) Na 2 S 2 O 4 , heat.
  • R CO 2 H i) 4-amino-1-benzenesulfonic acid, NaNO 2 , NaHCO 3 , water; ii) HCl, ice; iii) SnCl 2 , Aq. HCl, heat.
  • Scheme 1 outlines the preparation of the diamines used in the formation of Formula II or IIA compounds as shown in scheme 3.
  • the diamino compounds are prepared by diazo coupling of 4-benzenediazonium sulfate with the appropriate aminohydroxy naphthalene sulfonic acid under aqueous acidic conditions. The resulting diazo compounds are then reduced by sodium hydrogen sulfite in water to yield the corresponding diamines as their dihydrochloride salts.
  • ArB(OH) 2 Na 2 CO 3 , water, Pd(PPh 3 ) 4 , dioxane, heat;
  • BBr 3 CH 2 Cl 2
  • Scheme II outlines the formation of biaryl methoxy (or hydroxy) aldehydes for use in the preparation of Formula II or IIA compounds as shown in scheme 3.
  • a bromo methoxy aldehyde is subjected to Suzuki coupling conditions using an appropriate boronic acid such as 4-methylphenylboronic acid, in an appropriate solvent system such as dioxane and 1N aqueous sodium carbonate.
  • Palladium tetrakis triphenyl phosphine was used as the catalyst in the coupling reaction.
  • a portion of the biaryl methoxy aldehyde is then subjected to demethylation conditions using boron tribromide in methylene chloride at room temperature.
  • the above benzene moiety can be replaced by another moiety such as: furan, thiophene, pyridine, pyrazole and thiazole.
  • Scheme III outlines a preparation of compounds of Formula II or IIA.
  • a diamino-hydroxy naphthalene sulfonic acid prepared by the method of Scheme I is treated with 1.1 Eq. of a biaryl methoxy or hydroxy aldehyde prepared by the method of Scheme 2.
  • the reaction is run in the presence of a dehydrogenation reagent such as sodium pyrosulfite in a suitable solvent such as aqueous ethanol at 50 °C overnight to afford the desired naphthimidazole.
  • the precipitated naphthimidazole can then be filtered off and successive washings with water (to remove unwanted sodium salts) followed by ethyl eacetate (to remove unreacted aldehyde) provide compounds of formula I in > 80 % purity.
  • the treatment of thrombocytopenia is accomplished by enhancing the production of platelets.
  • co-administering and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a TPO mimetic compound, as described herein, and a further active ingredient or ingredients, known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • the pharmaceutically active compounds of the present invention are active as TPO mimetics they exhibit therapeutic utility in treating thrombocytopenia and other conditions with depressed platelet production.
  • Some of the most preferred compounds of this invention were also active in an in vitro proliferation assay using the murine 32D-mpl cell line (Bartley, T. D. et al., Cell, 1994, 77, 1117-1124). 32D-mpl cells express Tpo-R and their survival is dependent on the presence of TPO. Likewise, some of the most preferred compounds of this invention were also positive in stimulating the maturation of megakaryocytes from human bone marrow cells.
  • compositions within the scope of this invention are useful as TPO mimetics in mammals, including humans, in need thereof.
  • Some of the preferred compounds within the scope of the invention showed activation from about 4% to 130% control at a concentration of 0.01-10 uM in the luciferase assay.
  • the preferred compounds of the invention also promoted the proliferation of 32D-mpl cells at a concentration of 0.01 to 100 uM.
  • the preferred compounds of the invention also showed activity in the CD41 megakaryocytic assay at a concentration of 0.01 to 30 uM.
  • Compound 14 showed activation of about 25% of control (control is the maximal response to TPO) at a concentration of 2 uM in the luciferase assay.
  • the compounds of the present invention can be used in a method of treating thrombocytopenia and other conditions with depressed platelet production, which comprises administering a compound of Formula (II) or (IIA), as described above, in a quantity effective to enhance platelet production.
  • the compounds of Formula (II) or (IIA) can be used in a method of treating the above indicated disease states because of their demonstrated ability to act as TPO mimetics.
  • the drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
  • Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg.
  • the selected dose is administered preferably from 1-6 times daily, orally or parenterally.
  • Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion.
  • Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular TPO mimetic in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
  • the compounds can be used in a method of inducing TPO mimetic activity in mammals, including humans, comprising administering to a subject in need of such activity an effective TPO mimetic amount of a pharmaceutically active compound of the present invention.
  • the invention provides for the use of a compound of Formula (II) or (IIA) in the manufacture of a medicament for use as a TPO mimetic.
  • the compound of Formula (II) or (IIA) can be used in the manufacture of a medicament for use in therapy.
  • the invention also provides for the use of a compound of Formula (II) or (IIA) in the manufacture of a medicament, wherein the medicament is for use in administering to a mammal a therapeutically effective amount of the compound and is for use in enhancing platelet production in the mammal, and wherein the mammal, including a human, is in need of enhanced platelet production.
  • the invention also provides for the use of a compound of Formula (II) or (IIA) in the manufacture of a medicament for use in treating thrombocytopenia.
  • the invention also provides for a pharmaceutical composition for use as a TPO mimetic which comprises a compound of Formula (II) or (IIA) and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in the treatment of thrombocytopenia which comprises a compound of Formula (II) or (IIA) and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in administering to and enhancing platelet production in a mammal, including a human, in need of enhanced platelet production, which composition comprises a therapeutically effective amount of a compound of Formula (II) or (IIA) and a pharmaceutically acceptable carrier.
  • the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production, or compounds known to have utility when used in combination with a TPO mimetic.
  • further active ingredients such as other compounds known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production, or compounds known to have utility when used in combination with a TPO mimetic.
  • a stirred solution of p-benzenediazonium sulfonic acid was prepared by the addition of sodium sulfanilate (1.10 g, 5.2 mmole) to sodium nitrite (0.40 g, 5.7 mmole) in water (10 mL) followed by addition to ice (6.0 g) and concentrated HCl (1.1 mL, 37%). After 30 min. of standing at 0 °C 4-amino-5-hydroxy-1-naphthalene sulfonic acid (1.2 g, 5.2 mmole) was added in water (10 mL) and the reaction was stirred at room temperature over 18 hours.
  • a stirred solution of p-benzenediazonium sulfonic acid was prepared by the addition of sodium sulfanilate (1.10 g, 5.2 mmole) to sodium nitrite (0.40 g, 5.7 mmole) in water (10 mL) followed by addition to ice (6.0 g) and concentrated HCl (1.1 mL, 37%). After 30 min. of standing at 0 °C 7-amino-1-hydroxy-3-naphthalene sulfonic acid (1.2 g, 5.2 mmole) was added in water (10 mL) and the reaction was stirred at room temperature overnight.
  • a stirred solution of p-benzenediazonium sulfonamide was prepared by the addition of sulfanilamide (0.07 g, 0.4 mmole) in 10 % aqueous HCl (2.5 mL) to sodium nitrite (0.07 g, 0.5 mmole) in water (0.5 mL) at 0 °C. After 15 min. of standing at 0°C, 7-amino-1-hydroxy-3-naphthoic acid (0.07 g, 0.325 mmole) was added in water (1.0 mL) and the reaction was stirred at room temperature for 30 min.
  • reaction mixture was cooled and suspended between ethyl acetate and 3M aqu. hydrochloric acid (30 mL). The phases were separated and the aqueous phase was further extracted with ethyl acetate (3 times). The combined organic layers were dried over anhydrous MgSO 4 and concentrated under reduced pressure to give crude product.
  • Phosphorus oxychloride (0.075 ml, 0.5 mmol) was added dropwise slowly to a stirred solution of freshly distilled dimethylformamide (0.075 ml, 1.0 mmol) containing 1-(4-tert-butylphenyl)-1H-pyrazole (0.1 g, 0.5 mmol) at 90-100°C. After complete addition, the reaction mixture was stirred for another 4 hours under the same conditions. The reaction mixture was cooled and ice-water added. The pH was adjusted to 4 with a diluted sodium hydroxide solution and then extract with ethanol. The organic solution was washed with hydrochloric acid (1N), with a diluted solution of sodium bicarbonate and then dried over sodium sulfate.
  • An oral dosage form for administering a presently invented agonist of the TPO receptor is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.
  • Table I INGREDIENTS AMOUNTS 2-(3-[2'-Methylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazole-5-sulfonic acid hydrochloride 25 mg (Compound 1) Lactose 55 mg Talc 16 mg Magnesium Stearate 4 mg
  • Example 52 Injectable Parenteral Composition
  • An injectable form for administering a presently invented agonist of the TPO receptor is produced by stirring 1.5% by weight of 2-(3-[4'-Methylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazole-5-sulfonic acid hydrochloride (Compound 2) in 10% by volume propylene glycol in water.
  • sucrose, calcium sulfate dihydrate and a presently invented agonist of the TPO receptor are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
  • Preferred among the compounds of the present invention are the following.

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Claims (12)

  1. Medikament zur Verwendung in der Therapie, hergestellt unter Verwendung und umfassend eine Verbindung mit der folgenden Formel (II):
    Figure imgb0009
     worin
    R1, R2, R3, R4 und R5 jeweils unabhängig aus der Gruppe ausgewählt sind, die aus Carbonsäure, Sulfonsäure, Wasserstoff, C1-4-Alkoxy, C1-6-Alkyl und Halogen besteht;
    R6 Wasserstoff ist;
    R7 aus der Gruppe ausgewählt ist, die aus Wasserstoff, Alkyl, Cycloalkyl, C1-12-Aryl und substituiertem Alkyl besteht;
    m 0 bis 3 ist; und
    AR cyclisches oder polycyclisches aromatisches C3-C14 ist, das gegebenenfalls 1 bis 3 Heteroatome enthält, mit der Maßgabe, daß dann, wenn C 3 ist, der aromatische Ring wenigstens 2 Heteroatome enthält, und dann, wenn C 4 ist, der aromatische Ring wenigstens ein Heteroatom enthält, und das gegebenenfalls mit einem oder mehreren Substituenten substituiert ist, die aus der Gruppe ausgewählt sind, die aus Alkyl, substituiertem Alkyl, C1-12-Aryl, substituiertem Cycloalkyl, substituiertem C1-12-Aryl, Aryloxy, -NR11R11, Hydroxy, Alkoxy, Cycloalkyl, Amino, Nitro, Cyano und Halogen besteht, worin
    R11 aus der Gruppe ausgewählt ist, die aus Wasserstoff, Alkyl, Cycloalkyl, C1-12-Aryl, substituiertem Alkyl, substituiertem Cycloalkyl und substituiertem C1-12-Aryl besteht;
    und worin mit dem Begriff "Alkyl" und in Derivaten davon eine lineare oder verzweigte, gesättigte oder ungesättigte Kohlenwasserstoffkette gemeint ist, die, wenn nicht anders definiert, 1 bis 12 Kohlenstoffatome hat;
    und pharmazeutisch akzeptable Salze, Hydrate, Solvate und Ester davon.
  2. Medikament gemäß Anspruch 1, worin
    R1, R2, R3, R4 und R5 jeweils unabhängig aus Carbonsäure, Sulfonsäure, Wasserstoff, C1-3-Alkoxy, C1-3-Alkyl und Halogen ausgewählt sind;
    R6 Wasserstoff ist;
    R7 aus Wasserstoff, Alkyl und substituiertem Alkyl ausgewählt ist;
    m 0 ist; und
    AR aus Naphthalin, Phenyl, Pyridin und Pyrazol ausgewählt ist und gegebenenfalls mit einem bis drei Substituenten substituiert ist, die aus der Gruppe ausgewählt sind, die aus Alkyl, substituiertem Alkyl, C1-12-Aryl, substituiertem C1-12-Aryl, Hydroxy, Amino, -NR11R11, Alkoxy und Halogen besteht, worin
    R11 aus der Gruppe ausgewählt ist, die aus Wasserstoff, Alkyl, Cycloalkyl, C1-12-Aryl, substituiertem Alkyl, substituiertem Cycloalkyl und substituiertem C1-12-Aryl besteht.
  3. Verbindung mit der folgenden Formel (IIA):
    Figure imgb0010
     worin
    R1, R2, R3, R4 und R5 jeweils unabhängig aus Carbonsäure, Sulfonsäure, Wasserstoff, C1-3-Alkoxy, C1-3-Alkyl und Halogen ausgewählt sind;
    R6 Wasserstoff ist;
    R7 aus Wasserstoff, Alkyl und substituiertem Alkyl ausgewählt ist;
    m 0 ist; und
    AR aus Naphthalin, Phenyl, Pyridin und Pyrazol ausgewählt ist und gegebenenfalls mit 1 bis 3 Substituenten substituiert ist, die aus der Gruppe ausgewählt sind, die aus Alkyl, substituiertem Alkyl, C1-12-Aryl, substituiertem C1-12-Aryl, Hydroxy, Alkoxy und Halogen besteht;
    und worin mit dem Begriff "Alkyl" und in Derivaten davon eine lineare oder verzweigte, gesättigte oder ungesättigte Kohlenwasserstoffkette gemeint ist, die, wenn nicht anders definiert, 1 bis 12 Kohlenstoffatome hat;
    und pharmazeutisch akzeptable Salze, Hydrate, Solvate und Ester davon.
  4. Verbindung oder Medikament gemäß Anspruch 1, 2 oder 3, worin:
    mit dem Begriff "Alkyl" und in Derivaten davon -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, -C(CH3)3, -(CH2)3-CH3, -CH2-CH(CH3)2 oder -CH(CH3)-CH2-CH3 gemeint ist;
    "Cycloalkyl" Cyclohexyl oder Cyclopentyl bedeutet;
    "substituiertes Cycloalkyl" 4-Hydroxy-cyclohexyl, 2-Ethylcyclohexyl, Propyl-4-methoxycyclohexyl, 4-Methoxycyclohexyl oder 4-Carboxycyclohexyl bedeutet; und
    "Aryloxy" Phenoxy, 4-Fluorphenyloxy oder Biphenyloxy bedeutet.
  5. Verbindung oder Medikament gemäß Anspruch 1, 2, 3 oder 4, worin mit dem Begriff "substituiert" gemeint ist, daß die betroffene chemische Einheit einen Substituenten hat, der aus der Gruppe ausgewählt ist, die aus Hydroxyalkyl, Alkoxy, Acyloxy, Alkyl, Amino, N-Acylamino, Hydroxy, -(CH2)gC(O)OR6, -S(O)nR7, Nitro, Cyano, Halogen und Trifluormethyl besteht, worin g 0 ist, R6 Wasserstoff oder Alkyl ist, n 0-2 ist und R7 Wasserstoff oder Alkyl ist.
  6. Verbindung, die ausgewählt ist aus:
    2-(3-[2'-Methylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[4'-Methylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[3',4'-Dimethylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[3'-Methoxyphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[3'-Trifluormethylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[4'-Fluorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[4'-Chlorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[1'-Dibenzofuranyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[1'-Naphthalenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[3'-Chlorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[3'-Nitrophenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-Phenyl-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[2'-Methylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[4'-Methylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[3',4'-Dimethylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[3'-Methoxyphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[3'-Trifluormethylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[4'-Fluorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[4'-Chlorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[1'-Dibenzofuranyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[1'-Naphthalenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[3'-Chlorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[3'-Nitrophenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-Phenyl-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[2'-Methylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[4'-Methylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[3',4'-Dimethylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[3'-Methoxyphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[3'-Trifluormethylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[4'-Fluorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[4'-Chlorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[1'-Dibenzofuranyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[1'-Naphthalenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[3'-Chlorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[3'-Nitrophenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-Phenyl-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[2'-Methylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[4'-Methylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[3',4'-Dimethylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[3'-Methoxyphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[3'-Trifluormethylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[4'-Fluorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[4'-Chlorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[1'-Dibenzofuranyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[1'-Naphthalenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[3'-Chlorphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[3'-Nitrophenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-Phenyl-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[2'-Methylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[4'-Methylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[3',4'-Dimethylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[3'-Trifluormethylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[4'-Fluorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[4'-Chlorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[1'-Dibenzofuranyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[1'-Naphthalenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[3'-Chlorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[3'-Nitrophenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-Phenyl-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[2'-Methylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[4'-Methylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[3',4'-Dimethylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(3-[3'-Trifluormethylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[4'-Fluorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[4'-Chlorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[1'-Dibenzofuranyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[1'-Naphthalenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[3'-Chlorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-[3'-Nitrophenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-Phenyl-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[2'-Methylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[4'-Methylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[3'-Hydroxyphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[4'-Fluorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[4'-Chlorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[1'-Dibenzofuranyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[1'-Naphthalenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[3'-Chlorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[3'-Nitrophenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-Phenyl-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-5-sulfonsäurehydrochlorid;
    2-(4-[2'-Methylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[4'-Methylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[3'-Hydroxyphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[4'-Fluorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[4'-Chlorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[1'-Dibenzofuranyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[1'-Naphthalenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[3'-Chlorphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-[3'-Nitrophenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(4-Phenyl-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3-Phenyl-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-carbonsäurehydrochlorid;
    2-(3-[3',4'-Dimethylphenyl]-2-methoxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-carbonsäuretrifluoracetat;
    2-(3-[3',4'-Dimethylphenyl]-2-hydroxyphenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-carbonsäuretrifluoracetat;
    2-(1-[3,4-Dimethylphenyl]-3-methyl-5-hydroxy-1H-pyrrazol-4-yl)-9-hydroxy-3H-napth[1,2-d]imidazol-7-carbonsäuretrifluracetat;
    2-(1-Hydroxy-2-naphthalenyl)-9-hydroxy-naphth[1,2-d]imidazol-7-carbonsäuretrifluoracetat;
    2-(2-Pyridinyl)-9-hydroxy-naphth[1,2-d]imidazol-7-carbonsäuretrifluoracetat;
    2-(3',4'-Dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-Biphenyl-4-yl-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-sulfonsäurehydrochlorid,
    2-(3',4'-Dimethylbiphenyl-4-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-sulfonsäuretrifluoracetat;
    2-(4'-tert-Butylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-sulfonsäuretrifluoracetat;
    2-[3-(4-tert-Butylbenzyloxy)-phenyl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-[3-(3-Trifluormethylbenzyloxy)-phenyl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-[3-(3,4-Dimethylbenzyloxy)-phenyl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-sulfonsäurehydrochlorid;
    2-(3',4'-Dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäurehydrochlorid;
    2-(3',4'-Dimethylbiphenyl-4-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäuretrifluoracetat;
    2-(4'-tert-Butylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäuretrifluoracetat;
    9-Hydroxy-2-(3-phenoxyphenyl)-3H-naphtho[1,2-d]imidazol-7-carbonsäuretrifluoracetat;
    3-[2-(3',4'-Dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-sulfonylamino]-benzoesäure;
    1-[2-(3',4'-Dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-sulfonyl]-piperidin-3-carbonsäure;
    (S)-1-[2-(3',4'-Dimethyl-biphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-sulfonyl]-pyrrolidin-2-carbonsäure;
    ({1-[2-(3',4'-Dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-yl]-methanoyl}-amino)-essigsäure;
    (S)-2-({1-[2-(3',4'-Dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-yl]-methanoyl}-amino)-propionsäure;
    ({1-[2-(3',4'-Dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-yl]-methanoyl}-methylamino)-essigsäure;
    (S)-1-{1-[2-(3',4'-Dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-yl]-methanoyl}-pyrrolidin-2-carbonsäure;
    (S)-2-({1-[2-(4'-tert-Butylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-yl]-methanoyl}-amino)-pentandisäure;
    2-[6-(4-tert-Butylphenyl)-pyridin-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[5-(3,4-Dichlorphenyl)furan-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[5-Benzo[b]thiophen-2-furan-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    9-Hydroxy-2-[5-(4-tert-butylphenyl)-furan-2-yl)-furan-2-yl]-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    9-Hydroxy-2-[4-(4-tert-butylphenyl)-furan-2-yl]-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[5-(3,4-Dimethylphenyl)-furanl-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4-(3,4-Dimethylphenyl)-furan-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[5-(4-tert-Butylphenyl)-thiophen-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4-(4-tert-Butylphenyl)-thiophen-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[5-(3,4-Dimethylphenyl)-thiophen-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4-(3,4-Dimethylphenyl)-thiophen-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4'-tert-Butyl-6-methoxybiphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4'-tert-Butyl-6-fluor-biphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4'-tert-Butyl-4-fluorbiphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[6-Fluor-3',4'-dimethylbiphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4-Fluor-3',4'-dimethylbiphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4'-Trifluormethylbiphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    9-Hydroxy-2-[5-(3-isopropylphenyl)-furan-2-yl]-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    9-Hydroxy-2-[4-(4-tert-butylphenyl)-furan-2-yl]-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    9-Hydroxy-2-[5-(4-tert-butylphenyl)-furan-2-yl]-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[5-(3,4-Dimethylphenyl)-thiophen-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4-(3,4-Dimethylphenyl)-thiophen-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4-(4-tert-Butylphenyl)-thiophen-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[5-(4-tert-Butylphenyl)-thiophen-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[5-(3,4-Dichlorphenyl)furan-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[5-Benzo[b]thiophen-2-yl-furan-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4'-tert-Butyl-6-methoxybiphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[6-Fluor-3',4'-dimethylbiphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4-Fluor-3',4'-dimethylbiphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4'-tert-Butyl-4-fluorbiphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4'-Trifluormethylbiphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4'-tert-Butyl-6-fluor-biphenyl-3-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[5-(4-tert-Butylphenyl)-pyridin-3-yl]-9-hydroxy-1H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[(2-Fluor-4-trifluormethylbiphenyl)-3-yl]-9-hydroxy-1H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[(2,5-Difluor-4-trifluormethylbiphenyl)-3-yl]-9-hydroxy-1H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[(4-Fluor-4'-trifluormethylbiphenyl)-3-yl]-9-hydroxy-1H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[5-(4-Trifluormethylphenyl)-furan-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[4-(4-Trifluormethylphenyl)-thiophen-2-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-(4'-Ethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-(4'-Propylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-(4'-Butylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-(4'-Carboxy-3'-methylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-(4'-Cyano-3'-methylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-(4'-Fluor-3'-methylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-[1-(4-tert-Butylphenyl)-1H-pyrazol-4-yl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    2-(3',4'-Difluorbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure; und
    2-[3-(9H-Fluoren-2-yl)-phenyl]-9-hydroxy-3H-naphtho[1,2-d]imidazol-7-carbonsäure;
    und pharmazeutisch akzeptable Salze, Hydrate, Solvate und Ester davon.
  7. Pharmazeutische Zusammensetzung zur Verwendung in der Behandlung von Thrombozytopenie, die eine Verbindung wie in einem der Ansprüche 1 bis 6 definiert und einen pharmazeutisch akzeptablen Träger umfaßt.
  8. Pharmazeutische Zusammensetzung zur Verwendung in der Verabreichung an und Steigerung der Blutplättchenproduktion in einem Säugetier, einschließlich Mensch, das der gesteigerten Blutplättchenproduktion bedarf,
    wobei die Zusammensetzung eine therapeutisch wirksame Menge einer Verbindung wie in einem der Ansprüche 1 bis 6 definiert und einen pharmazeutisch akzeptablen Träger umfaßt.
  9. Pharmazeutische Zusammensetzung gemäß einem der Ansprüche 7 bis 8, die eine orale Dosierungseinheit zur humanen Verabreichung ist.
  10. Pharmazeutische Zusammensetzung gemäß einem der Ansprüche 7 bis 8 zur parenteralen Verabreichung.
  11. Verwendung einer Verbindung wie in einem der Ansprüche 1 bis 6 definiert in der Herstellung eines Medikaments zur Verwendung in der Behandlung von Thrombozytopenie.
  12. Verwendung einer Verbindung wie in einem der Ansprüche 1 bis 6 definiert in der Herstellung eines Medikaments, worin das Medikament zur Verwendung in der Verabreichung einer therapeutisch wirksamen Menge der Verbindung an ein Säugetier dient und zur Verwendung in der Steigerung der Blutplättchenproduktion im Säugetier dient und worin das Säugetier, einschließlich Mensch, der gesteigerten Blutplättchenproduktion bedarf.
EP00984123A 1999-12-06 2000-12-06 Thrombopoietin-mimetika Expired - Lifetime EP1244446B1 (de)

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Application Number Priority Date Filing Date Title
US16913099P 1999-12-06 1999-12-06
US169130P 1999-12-06
PCT/US2000/033432 WO2001039773A1 (en) 1999-12-06 2000-12-06 Thrombopoietin mimetics

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EP1244446A4 EP1244446A4 (de) 2003-01-08
EP1244446B1 true EP1244446B1 (de) 2006-11-02

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JP (1) JP2003515560A (de)
AT (1) ATE344031T1 (de)
AU (1) AU2079901A (de)
DE (1) DE60031714T2 (de)
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WO (1) WO2001039773A1 (de)

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TW200418791A (en) * 2003-01-23 2004-10-01 Bristol Myers Squibb Co Pharmaceutical compositions for inhibiting proteasome
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PL1910338T3 (pl) 2005-07-14 2011-02-28 Irm Llc Związki heterotetracykliczne jako mimetyki TPO
JP5071375B2 (ja) 2005-07-15 2012-11-14 日産化学工業株式会社 チオフェン化合物及びトロンボポエチンレセプター活性化剤
JP5104752B2 (ja) 2005-07-20 2012-12-19 日産化学工業株式会社 ピラゾール化合物及びトロンボポエチンレセプター活性化剤
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JP5157900B2 (ja) 2006-06-07 2013-03-06 日産化学工業株式会社 含窒素ヘテロ環化合物及びトロンボポエチンレセプター活性化剤
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ES2275567T3 (es) 2007-06-16
EP1244446A4 (de) 2003-01-08
DE60031714T2 (de) 2007-09-06
EP1244446A1 (de) 2002-10-02
AU2079901A (en) 2001-06-12
DE60031714D1 (de) 2006-12-14
ATE344031T1 (de) 2006-11-15
JP2003515560A (ja) 2003-05-07

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